LTA.sub.4 hydrolase is a requisite enzyme in the biosynthetic pathway leading to LTB.sub.4 formation. LTB.sub.4 is a proinflammatory compound. R. Lewis, et al., N. Engl. J. Med. 323, 645-655 (1990) have demonstrated that LTB.sub.4 is a potent granulocyte agonist inducing chemotaxis, aggregation, degranulation, adherence and priming of inflammatory cells for induction by other agonists. Binding of LTB.sub.4 to receptors is stereospecific with two distinct classes of binding sites. A. Lin, et al., Prostaglandins 28, 837-849 (1984). A high affinity site 4-5.times.10.sup.-10 M! mediates chemotaxis and chemokinesis while lower affinity sites 0.6-5.times.10.sup.-7 M! stimulate granular secretion and oxidative burst. The LTB.sub.4 receptor is associated with a GTP-binding protein that regulates affinity and transduces signals. T. Schepers, et al., J. Biol. Chem. 267, 159-165 (1992). Elevated LTB.sub.4 levels have been reported for many diseases. Most prominently, elevated LTB.sub.4 levels have been correlated to the pathology of inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis and in psoriasis. P. Sharon, et al., Gastroent. 86, 453-460; K. Lauritsen, et al., Gastroent. 95, 11-17 (1989); S. Brain, et al., Br. J. Pharm., 83, 313-317 (1984). Other properties of LTB.sub.4 which may contribute to disease processes are: stimulation of mucus secretion; stimulation of cytokine production; and the ability to act synergistically with other inflammatory mediators such as prostaglandins and cysteinyl leukotrienes thereby amplifying the inflammatory process.
B. Samuelsson, et al., J. Biol Chem., 264, 19469-19472 (1989) have shown that LTB.sub.4 biosynthesis from arachidonic acid involves the action of 2 enzymes, 5-lipoxygenase 5-LO! and LTA.sub.4 hydrolase. 5-LO transforms arachidonic acid to 5-HPETE and subsequent formation of LTA.sub.4, which is an unstable allylic epoxide intermediate which is enzymatically hydrolyzed by LTA.sub.4 hydrolase to form the dihydroxy acid LTB.sub.4.
LTA.sub.4 hydrolase is distinct from cytosolic and microsomal epoxide hydrolases based on strict substrate requirements, product formation 5(S),12(R) vs. 5(S),6(R)! for mouse liver cytosolic epoxide hydrolase, and lack of inhibition by inhibitors of cytosolic epoxide hydrolase. LTA.sub.4 hydrolase appears to be ubiquitously distributed in mammalian tissues even in cell types that do not express 5-LO, suggesting the importance of transcellular metabolism of LTA.sub.4. While peptidomimetic compounds such as bestatin and captopril have been shown to exhibit LTA.sub.4 hydrolase inhibitory activity, they are not able to satisfy the requirement of a small organic compound which is capable of cellular penetration. It would therefore be very advantageous to be able to provide low molecular weight inhibitors of LTB.sub.4 biosynthesis which preferably exhibit oral activity in vivo at desirably low concentrations.